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Evevident
Original paper
2020NEJMCardiology

EMPEROR-Reduced

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure

RCTHeart Failure

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Overview

Empagliflozin reduced cardiovascular death or heart-failure hospitalization in symptomatic HFrEF, with or without diabetes.

Clinical takeaway

EMPEROR-Reduced showed that empagliflozin improves HFrEF outcomes on top of standard therapy, reducing the primary composite mainly through fewer heart-failure hospitalizations and slowing kidney-function decline.

Key result

Primary composite: 19.4% vs 24.7%; HR 0.75 (95% CI 0.65-0.86), p<0.001.

Practice impact

Reinforced SGLT2 inhibitors as foundational HFrEF therapy independent of diabetes status.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial.

Enrollment

3,730

Follow-up

Median 16 months

Geography

Multinational

Clinical question

In symptomatic chronic heart failure with reduced ejection fraction, does empagliflozin reduce cardiovascular death or hospitalization for heart failure compared with placebo?

Population

  • Adults with NYHA class II-IV chronic heart failure
  • LVEF <= 40% with elevated natriuretic peptide levels
  • On recommended heart-failure background therapy
  • Included patients with and without type 2 diabetes

Intervention

Empagliflozin 10 mg once daily.

Comparator

Placebo.

Primary outcome

Composite of cardiovascular death or hospitalization for heart failure.

Empagliflozin reduced cardiovascular death or hospitalization for heart failure compared with placebo.

HR / 0.75 / CI 0.65-0.86 / p=<0.001

Key results

  • Primary composite: 19.4% with empagliflozin vs 24.7% with placebo; HR 0.75 (95% CI 0.65-0.86), p<0.001.
  • First hospitalization for heart failure was reduced: HR 0.69 (95% CI 0.59-0.81).
  • The annual rate of eGFR decline was slower with empagliflozin.
  • Benefit was consistent in patients with and without diabetes.

Harms

  • Uncomplicated genital tract infection was reported more often with empagliflozin.

Clinical Use

When to cite

  • When explaining why empagliflozin is part of foundational HFrEF therapy.
  • When comparing the HFrEF SGLT2 evidence base with DAPA-HF.
  • When emphasizing SGLT2 inhibitor benefit regardless of diabetes status.

Practice impact

  • Helped establish SGLT2 inhibitors as one of the core pillars of HFrEF guideline-directed medical therapy.
  • Extended empagliflozin use beyond diabetes-centered cardiovascular risk reduction into direct heart-failure treatment.
  • Complemented DAPA-HF by showing HFrEF benefit with another SGLT2 inhibitor.

Applicability

  • Most applicable to stable symptomatic HFrEF patients already receiving standard background therapy.
  • Applies whether or not the patient has type 2 diabetes.
  • Particularly useful when discussing prevention of heart-failure hospitalization and preservation of kidney function.

Limitations

  • Median follow-up was relatively short.
  • Primary outcome benefit was driven more by heart-failure hospitalization than cardiovascular death alone.
  • Trial eligibility required elevated natriuretic peptides and excluded patients with very low blood pressure or eGFR < 20 mL/min/1.73 m2.

Common misinterpretations

  • Do not limit empagliflozin's HFrEF role to patients with diabetes.
  • Do not cite EMPEROR-Reduced as a mortality-only trial; the clearest signal was reduced HF hospitalization.

Related evidence

DAPA-HF - Same Drug ClassEMPEROR-Preserved - Later TrialEMPA-REG OUTCOME - Earlier TrialPARADIGM-HF - Same Disease

Citation

Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190

Empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure.